DETERMINANTS AND MECHANISMS OF HUMAN IMMUNE-RESPONSES TO BEE VENOM PHOSPHOLIPASE A(2)

The elicitation of an immune response to protein antigens depends on t he specific recognition of antigenic determinants (epitopes) by T and B lymphocytes. Bee venom phospholipase A(2) (PLA) represents the major antigen/allergen of honey bee venom. It displays three dominant immun ogenic peptide and one glycopeptide T cell recognition sites. These ep itopes are equally recognized by both allergic and nonallergic individ uals. A mixture of the three epitope containing peptides was successfu lly used in specific immunotherapy of bee venom-allergic patients. Bot h peptide and whole bee venom immunotherapy induced a state of specifi c anergy in T cells, The production of specific IgE and IgG4 antibodie s directly correlated with the secreted interleukin-4:gamma-interferon (IL-4:IFN gamma) ratio, which itself depended on the concentration of available antigen and the strength of the T cell-activating signal. T his signal comprises accumulated molecular interactions delivered by e ngagement of the antigenic peptide/MHC class II complex with the T cel l receptor (TcR). Indeed the thermodynamic laws of chemical equilibriu m reactions reveal that the antigen concentration, together with the e quilibration constant Ki and the related Gibbs standard free energy De lta G degrees of the MHC-II/Ag/TcR complex reaction, may govern the se creted IL-4:IFN gamma ratio, and in consequence, differential IgE and IgG4 antibody formation. K-i includes epitope and MHC-II haplotype var iability and therefore represents a measure of immunological individua lity. A major B cell epitope was determined by using point-mutated PLA . Specific antigen recognition by B cells can trigger distinct cytokin e profiles in T cells and contribute to the differential regulation of specific IgE and IgG4 antibodies. Our results indicate that distinct cytokine profiles inducing allergic and nonallergic responses can be a ttributed to thresholds of T cell activation generated by the specific binding properties of individual MHC-II molecules to immunogenic T ce ll epitopes and their presentation to TcR.